doi: 10.1111/fcp.12083
Fundamental & Clinical Pharmacology
CASE REPORT
Bullous pemphigoid induced by vildagliptin: a report of three cases Johana Benea*, Aurelie Jacobsooneb, Patrick Coupec, Marine Auffreta, Samy Babaid, Dominique Hillaire-Buyse, Marie-Josephe Jean-Pastorf, Marlene Vonarxg, Annie Vermerschg, Anne-Fleur Tronquoyg, Sophie Gautiera a Departement de Pharmacologie, Faculte de Medecine, Centre Regional de PharmacoVigilance, Centre Hospitalier Universitaire de Lille, Universite de Lille 2, 1, place de Verdun, 59037 Lille, France b Service de Dermatologie, H^opital Huriez, Centre Hospitalier Universitaire de Lille, 59037 Lille, France c Service Pharmacie, Centre Hospitalier de Valenciennes, Avenue Desadrouin, 59300 Valenciennes, France d Centre Regional de PharmacoVigilance, H^opital Henri Mondor, Assistance Publique des H^opitaux de Paris, 51, av. du Marechal-de- Lattre-de-Tassigny, 94010 Creteil, France e Departement de Pharmacologie Medicale et Toxicologie, Faculte de Medecine et CHRU, Centre Regional de PharmacoVigilance, H^opital Lapeyronie, 371 avenue du Doyen Gaston Giraud, 34295 Montpellier cedex 5, France f Centre Regional de PharmacoVigilance, H^opital Salvator, Assistance Publique des H^opitaux de Marseille, 270 bld Sainte Marguerite, BP51, 13274 Marseille cedex 9, France g Service de Dermatologie, Centre Hospitalier de Valenciennes, Avenue Desadrouin, 59300 Valenciennes, France
Keywords adverse reactions, bullous pemphigoid, drug-induced skin disorder, gliptins
Received 3 January 2014; revised 16 May 2014; accepted 20 May 2014
*Correspondence and reprints: [email protected]
ABSTRACT
To report three cases of bullous pemphigoid in patients treated with vildagliptin. Case 1: An 86-year-old woman presented with bullous pemphigoid after 1 month of treatment with vildagliptin and metformin. After introduction of clobetasol, the symptoms resolved although vildagliptin was continued. However, the skin lesions reappeared 3 months later. Sustained remission was achieved only after definitive withdrawal of vildagliptin. Case 2: A 79-year-old man presented with bullous pemphigoid after 37month treatment with gliclazide, vildagliptin and metformin. The disease at first responded to clobetasol but 3 months later the lesions reappeared. They finally regressed when the gliptin was discontinued. Case 3: A 77-year-old woman, treated with gliclazide and vildagliptin for 26 months, presented with bullous pemphigoid, which responded well to discontinuation of the gliptin and topical clobetasol. Gliptins are new molecules for treatment of type 2 diabetes mellitus, which have been suspected of implication in bullous pemphigoid. Such cases have been described in the literature (seven with vildagliptin and three with sitagliptin). In nine of these cases, the gliptin was associated with metformin, but the latter had never been considered responsible. The mechanism implicated in the development of bullous pemphigoid has not yet been clearly identified, but may involve a modified immune response or alteration of the antigenic properties of the epidermal basement membrane. These reports support the risk of bullous pemphigoid in patients exposed to gliptins.
CASE REPORTS Case 1 An 86-year-old woman with type 2 diabetes had been treated for 2 months with vildagliptin 50 mg 9 2/day and metformin 1000 mg 9 2/day. She was admitted to hospital with a 1-month history te Francßaise de Pharmacologie et de The rapeutique ª 2014 Socie Fundamental & Clinical Pharmacology
of an erythematous bullous eruption, with bullae on healthy skin and extensive erosions on the body. She had a history of Alzheimer’s disease treated with memantine and rivastigmine. She was also treated with nifedipine, latanoprost and brinzolamide ophthalmic solutions, exemestane, lysine acetylsalicylate, irbesartan hydrochlorothiazide, simvastatin and
1
2
carbidopa-levodopa, and was taking iron supplements. On admission, the patient had no fever, no mucosal involvement, no adenopathies or increased eosinophil level. Nikolsky’s sign was not present. Direct immunofluorescence (DIF) and indirect immunofluorescence (IIF) were compatible with bullous pemphigoid. The patient’s condition improved after withdrawal of vildagliptin and topical treatment with clobetasol. Vildagliptin was replaced by insulin and metformin was continued. Case 2 A 79-year-old man had been treated for type 2 diabetes for 37 months with gliclazide 120 mg/day, vildagliptin 50 mg 9 2/day and metformin 1000 mg 9 2/day. He was admitted to hospital for a generalized erythematous vesicular bullous eruption of 3-week duration. He was also receiving long-term treatment with allopurinol, fluindione and atorvastatin, and was taking potassium, vitamin B12 and ergocalciferol supplements. The skin eruption was located on the trunk and the upper and lower limbs, particularly proximally, and suggested bullous pemphigoid. This was confirmed by skin biopsy, and DIF. Standard histology revealed a plane of cleavage below the epidermal basement membrane with an abundant inflammatory infiltrate of lymphocytes, plasma cells, histiocytes and polynuclear eosinophils. On admission, the patient had no fever and no mucosal involvement or adenopathy. Laboratory tests showed eosinophilia at 2.3 G/L. Local treatment with clobetasol initially controlled the disease, then the lesions recurred at 3 months in spite of very gradual tapering of clobetasol. The patient’s condition improved after discontinuation of vildagliptin. Case 3 A 77-year-old woman was hospitalized for a 3-month history of an extensive pruriginous bullous eruption suggesting bullous pemphigoid. The patient had a history of type 2 diabetes, arterial hypertension and dyslipidemia, and had been treated with gliclazide 60 mg 9 2/day and vildagliptin 50 mg 9 2/day for 26 months, as well as long-term atorvastatin, ramipril, fluindione, pantoprazole and pregabalin. Skin biopsy, DIF and IIF confirmed bullous pemphigoid. The biopsy specimen showed an epidermis with focal areas of slight spongiosis and exocytosis of some polynuclear eosinophils. Within the superficial, dermis was a slight pericapillary lymphoid infiltrate associated
J. Bene et al.
with fairly numerous polynuclear eosinophils. The patient had no fever. Her condition improved after discontinuation of vildagliptin (replaced by insulin) and topical clobetasol. These three patients are currently still well controlled with clobetasol, whose use is gradually tapered. DISCUSSION Gliptins, dipeptidyl peptidase-4 (DPP-4) inhibitors, are indicated in type 2 diabetes mellitus in the adult, in combination with another oral antidiabetic medication or with insulin. When gliptins were first marketed, they were not known to induce bullous pemphigoid, the most common of autoimmune bullous skin disorders. Up to now, seven cases of bullous pemphigoid during treatment with vildagliptin and three with sitagliptin had been reported in the literature [1–3]. In nine of these cases, the gliptin was associated with metformin. Time to occurrence of bullous pemphigoid ranged from two to 13 months after the start of treatment. In two of our cases, gliptin was associated with metformin. It seems unlikely that metformin was responsible in these cases, as the skin reaction systematically regressed on discontinuation of gliptin even though metformin was continued. Moreover, it is noteworthy that bullous pemphigoid during treatment with metformin alone has never been described in the literature in spite of the fact that this drug has been on the market for nearly 20 years. The responsibility of vildagliptin in these three cases is thus probable from a chronological viewpoint, as discontinuation of the drug was systematically followed by symptom resolution. The simultaneous introduction of topical steroids when the gliptin was discontinued could be considered as a confounding factor; however, the skin reaction did not reappear in spite of decreasing use of the topical steroids. In the skin, many cell types (including keratinocytes) express DPP-4, giving rise to cytokine production, tissue differentiation and collagen metabolism. Some factors that are modulated by DPP-4 in vivo such as proglucagon, GLP-1 and the GLP-1 receptor have also been described in cutaneous structures [4]. The biological pluripotency of gliptins may lead to a modification of immune response and/or an alteration of antigenic properties of the epidermal basement membrane that result in bullous pemphigoid.
te Francßaise de Pharmacologie et de The rapeutique ª 2014 Socie Fundamental & Clinical Pharmacology
Bullous pemphigoid induced by vildagliptine
CONCLUSION These reports support the hypothesis that there is a risk of bullous pemphigoid in patients exposed to gliptins. Health professionals must be aware of this risk, in particular endocrinologists, dermatologists and general practitioners, as this adverse effect is not as yet mentioned in the monographs on this class of drugs. REFERENCES 1 Skandalis K., Spirova M., Gaitanis G., Tsartsarakis A., Bassukas I.D. Drug-induced bullous pemphigoid in diabetes mellitus patients receiving dipeptidyl peptidase-IV inhibitors plus
te Francßaise de Pharmacologie et de The rapeutique ª 2014 Socie Fundamental & Clinical Pharmacology
3
metformin. J. Eur. Acad. Dermatol. Venereol. (2012) 26 249– 253. 2 Pasmatzi E., Monastirli A., Habeos J., Georgiou S., Tsambaos D. Dipeptidyl peptidase-4 inhibitors cause bullous pemphigoid in diabetic patients: report of two cases. Diabetes Care (2011) 34 133. 3 Aouidad I., Fite C., Marinho E., Deschamps L., Crickx B., Descamps V. A case report of bullous pemphigoid induced by dipeptidyl peptidase-4 inhibitors. JAMA Dermatol. (2013) 149 243–245. 4 List J.F., He H., Habener J.F. Glucagon-like peptide-1 receptor and proglucagon expression in mouse skin. Regul. Pept. (2006) 134 149–157.
Fundamental & Clinical Pharmacology
CASE REPORT
Bullous pemphigoid induced by vildagliptin: a report of three cases Johana Benea*, Aurelie Jacobsooneb, Patrick Coupec, Marine Auffreta, Samy Babaid, Dominique Hillaire-Buyse, Marie-Josephe Jean-Pastorf, Marlene Vonarxg, Annie Vermerschg, Anne-Fleur Tronquoyg, Sophie Gautiera a Departement de Pharmacologie, Faculte de Medecine, Centre Regional de PharmacoVigilance, Centre Hospitalier Universitaire de Lille, Universite de Lille 2, 1, place de Verdun, 59037 Lille, France b Service de Dermatologie, H^opital Huriez, Centre Hospitalier Universitaire de Lille, 59037 Lille, France c Service Pharmacie, Centre Hospitalier de Valenciennes, Avenue Desadrouin, 59300 Valenciennes, France d Centre Regional de PharmacoVigilance, H^opital Henri Mondor, Assistance Publique des H^opitaux de Paris, 51, av. du Marechal-de- Lattre-de-Tassigny, 94010 Creteil, France e Departement de Pharmacologie Medicale et Toxicologie, Faculte de Medecine et CHRU, Centre Regional de PharmacoVigilance, H^opital Lapeyronie, 371 avenue du Doyen Gaston Giraud, 34295 Montpellier cedex 5, France f Centre Regional de PharmacoVigilance, H^opital Salvator, Assistance Publique des H^opitaux de Marseille, 270 bld Sainte Marguerite, BP51, 13274 Marseille cedex 9, France g Service de Dermatologie, Centre Hospitalier de Valenciennes, Avenue Desadrouin, 59300 Valenciennes, France
Keywords adverse reactions, bullous pemphigoid, drug-induced skin disorder, gliptins
Received 3 January 2014; revised 16 May 2014; accepted 20 May 2014
*Correspondence and reprints: [email protected]
ABSTRACT
To report three cases of bullous pemphigoid in patients treated with vildagliptin. Case 1: An 86-year-old woman presented with bullous pemphigoid after 1 month of treatment with vildagliptin and metformin. After introduction of clobetasol, the symptoms resolved although vildagliptin was continued. However, the skin lesions reappeared 3 months later. Sustained remission was achieved only after definitive withdrawal of vildagliptin. Case 2: A 79-year-old man presented with bullous pemphigoid after 37month treatment with gliclazide, vildagliptin and metformin. The disease at first responded to clobetasol but 3 months later the lesions reappeared. They finally regressed when the gliptin was discontinued. Case 3: A 77-year-old woman, treated with gliclazide and vildagliptin for 26 months, presented with bullous pemphigoid, which responded well to discontinuation of the gliptin and topical clobetasol. Gliptins are new molecules for treatment of type 2 diabetes mellitus, which have been suspected of implication in bullous pemphigoid. Such cases have been described in the literature (seven with vildagliptin and three with sitagliptin). In nine of these cases, the gliptin was associated with metformin, but the latter had never been considered responsible. The mechanism implicated in the development of bullous pemphigoid has not yet been clearly identified, but may involve a modified immune response or alteration of the antigenic properties of the epidermal basement membrane. These reports support the risk of bullous pemphigoid in patients exposed to gliptins.
CASE REPORTS Case 1 An 86-year-old woman with type 2 diabetes had been treated for 2 months with vildagliptin 50 mg 9 2/day and metformin 1000 mg 9 2/day. She was admitted to hospital with a 1-month history te Francßaise de Pharmacologie et de The rapeutique ª 2014 Socie Fundamental & Clinical Pharmacology
of an erythematous bullous eruption, with bullae on healthy skin and extensive erosions on the body. She had a history of Alzheimer’s disease treated with memantine and rivastigmine. She was also treated with nifedipine, latanoprost and brinzolamide ophthalmic solutions, exemestane, lysine acetylsalicylate, irbesartan hydrochlorothiazide, simvastatin and
1
2
carbidopa-levodopa, and was taking iron supplements. On admission, the patient had no fever, no mucosal involvement, no adenopathies or increased eosinophil level. Nikolsky’s sign was not present. Direct immunofluorescence (DIF) and indirect immunofluorescence (IIF) were compatible with bullous pemphigoid. The patient’s condition improved after withdrawal of vildagliptin and topical treatment with clobetasol. Vildagliptin was replaced by insulin and metformin was continued. Case 2 A 79-year-old man had been treated for type 2 diabetes for 37 months with gliclazide 120 mg/day, vildagliptin 50 mg 9 2/day and metformin 1000 mg 9 2/day. He was admitted to hospital for a generalized erythematous vesicular bullous eruption of 3-week duration. He was also receiving long-term treatment with allopurinol, fluindione and atorvastatin, and was taking potassium, vitamin B12 and ergocalciferol supplements. The skin eruption was located on the trunk and the upper and lower limbs, particularly proximally, and suggested bullous pemphigoid. This was confirmed by skin biopsy, and DIF. Standard histology revealed a plane of cleavage below the epidermal basement membrane with an abundant inflammatory infiltrate of lymphocytes, plasma cells, histiocytes and polynuclear eosinophils. On admission, the patient had no fever and no mucosal involvement or adenopathy. Laboratory tests showed eosinophilia at 2.3 G/L. Local treatment with clobetasol initially controlled the disease, then the lesions recurred at 3 months in spite of very gradual tapering of clobetasol. The patient’s condition improved after discontinuation of vildagliptin. Case 3 A 77-year-old woman was hospitalized for a 3-month history of an extensive pruriginous bullous eruption suggesting bullous pemphigoid. The patient had a history of type 2 diabetes, arterial hypertension and dyslipidemia, and had been treated with gliclazide 60 mg 9 2/day and vildagliptin 50 mg 9 2/day for 26 months, as well as long-term atorvastatin, ramipril, fluindione, pantoprazole and pregabalin. Skin biopsy, DIF and IIF confirmed bullous pemphigoid. The biopsy specimen showed an epidermis with focal areas of slight spongiosis and exocytosis of some polynuclear eosinophils. Within the superficial, dermis was a slight pericapillary lymphoid infiltrate associated
J. Bene et al.
with fairly numerous polynuclear eosinophils. The patient had no fever. Her condition improved after discontinuation of vildagliptin (replaced by insulin) and topical clobetasol. These three patients are currently still well controlled with clobetasol, whose use is gradually tapered. DISCUSSION Gliptins, dipeptidyl peptidase-4 (DPP-4) inhibitors, are indicated in type 2 diabetes mellitus in the adult, in combination with another oral antidiabetic medication or with insulin. When gliptins were first marketed, they were not known to induce bullous pemphigoid, the most common of autoimmune bullous skin disorders. Up to now, seven cases of bullous pemphigoid during treatment with vildagliptin and three with sitagliptin had been reported in the literature [1–3]. In nine of these cases, the gliptin was associated with metformin. Time to occurrence of bullous pemphigoid ranged from two to 13 months after the start of treatment. In two of our cases, gliptin was associated with metformin. It seems unlikely that metformin was responsible in these cases, as the skin reaction systematically regressed on discontinuation of gliptin even though metformin was continued. Moreover, it is noteworthy that bullous pemphigoid during treatment with metformin alone has never been described in the literature in spite of the fact that this drug has been on the market for nearly 20 years. The responsibility of vildagliptin in these three cases is thus probable from a chronological viewpoint, as discontinuation of the drug was systematically followed by symptom resolution. The simultaneous introduction of topical steroids when the gliptin was discontinued could be considered as a confounding factor; however, the skin reaction did not reappear in spite of decreasing use of the topical steroids. In the skin, many cell types (including keratinocytes) express DPP-4, giving rise to cytokine production, tissue differentiation and collagen metabolism. Some factors that are modulated by DPP-4 in vivo such as proglucagon, GLP-1 and the GLP-1 receptor have also been described in cutaneous structures [4]. The biological pluripotency of gliptins may lead to a modification of immune response and/or an alteration of antigenic properties of the epidermal basement membrane that result in bullous pemphigoid.
te Francßaise de Pharmacologie et de The rapeutique ª 2014 Socie Fundamental & Clinical Pharmacology
Bullous pemphigoid induced by vildagliptine
CONCLUSION These reports support the hypothesis that there is a risk of bullous pemphigoid in patients exposed to gliptins. Health professionals must be aware of this risk, in particular endocrinologists, dermatologists and general practitioners, as this adverse effect is not as yet mentioned in the monographs on this class of drugs. REFERENCES 1 Skandalis K., Spirova M., Gaitanis G., Tsartsarakis A., Bassukas I.D. Drug-induced bullous pemphigoid in diabetes mellitus patients receiving dipeptidyl peptidase-IV inhibitors plus
te Francßaise de Pharmacologie et de The rapeutique ª 2014 Socie Fundamental & Clinical Pharmacology
3
metformin. J. Eur. Acad. Dermatol. Venereol. (2012) 26 249– 253. 2 Pasmatzi E., Monastirli A., Habeos J., Georgiou S., Tsambaos D. Dipeptidyl peptidase-4 inhibitors cause bullous pemphigoid in diabetic patients: report of two cases. Diabetes Care (2011) 34 133. 3 Aouidad I., Fite C., Marinho E., Deschamps L., Crickx B., Descamps V. A case report of bullous pemphigoid induced by dipeptidyl peptidase-4 inhibitors. JAMA Dermatol. (2013) 149 243–245. 4 List J.F., He H., Habener J.F. Glucagon-like peptide-1 receptor and proglucagon expression in mouse skin. Regul. Pept. (2006) 134 149–157.
